PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is the 6th leading cause of death in the United States, and is estimated to cost more than $200B/year. Uniquely among the top ten causes of death, we have little ability to treat or prevent the disease. Although the precise etiology of AD is still under investigation, strong evidence suggests that inflammation plays a critical role in the progression of the disease. Chronic low-grade inflammation increases systemically with age and correlates with most age-related diseases. This includes AD. One recognized driver of the age-related increase is systemic inflammation. Accumulating evidence indicates that loss of peripheral proteostasis could be a key source of systemic inflammation; in particular experimental data in model organisms show that proteostatic decline in both the intestine as well as skeletal muscle could be important sources of systemic inflammation, which in turn triggers inflammatory signaling in the central nervous system (CNS), affecting health, function and behavior, as well as A? plaque deposition and microglial activation. This supports a connection between intestinal-initiated inflammation and AD, but mechanistic insights remain poor. Here, the applicants propose to test the hypothesis that age-related proteostatic decline in the intestinal epithelium as well as in skeletal muscle are sources of inflammatory cytokines that result in elevated inflammation in the central nervous system (CNS) and thus increases AD progression and pathology. To test this hypothesis, the applicants propose studies in fruit flies, which allow tissue-specific genetic perturbations and characterization in exquisite detail. Furthermore, Drosophila neurobiology is well-described, several AD models are available, and most signaling pathways involved, including the ER unfolded protein response (UPRER) and the JAK/STAT inflammatory pathways, are conserved, but show less redundancy and complexity in flies than in vertebrates. Published work and preliminary data generated by the applicants suggest that age-related dysfunction of the intestinal microbiota is associated with strong chronic activation of the UPRER in the intestinal epithelium, and causes inflammation in the brain, influencing neuronal health and function in a Drosophila model of AD. In addition, applicants present preliminary data that links synaptic calcium influx to the regulation of muscle proteostasis as a novel mechanism to control age-related decline of muscle proteostasis. Using these novel methods, the preliminary findings by the applicants demonstrate that attenuating muscle proteostasis in aged flies can decrease the inflammatory load in the brain, improve locomotion behavior and extend lifespan. The applicants propose a mechanistic study to delineate the signaling pathways and physiological consequences of the loss of intestinal and muscle proteostasis on the brain. Based on the conserved signaling mechanisms studied, it can be anticipated that the findings of this study will pave the way for the development of novel interventions that could alleviate the symptoms of AD.